DESCRIPTION (investigator's abstract): Wegener's Granulomatosis is one of the anti-neutrophil cytoplasmic antibody (ANCA) positive systemic vasculitides which is characterized by inflammatory lesions with granuloma formation in the upper and lower airways, by pauci-immune glomerulonephritis and by anti-proteinase 3 autoantibodies (PR#-ANCA). Although WG is idiopathic, there has been substantial interest in environmental factors as either etiologic or accelerating risk factors. Because of epidemiological studies implicating nasal carriage and therapeutic studies implicating efficacy of anti-staphylococcal agents at least for upper airway disease, Staphylococcus aureus has attracted substantial attention as one such environmental factor. Although consensus about etiology remains elusive, the nature of the host response has emerged as an important determinant for disease phenotype and severity. There are may examples of human disease, provoked by environmental exposures, which have important genetic factors contributing to both susceptibility and severity. HIV presents one such example. Thus the identification of important genetic factors in a disease such as WG is not only feasible but also potentially very fruitful in providing insights into pathogenesis and potential therapeutic targets. Building on the clinical trial of Etanercept in WG (Wegener's Granulomatosis Etanercept Trial, WGET), we propose to develop a renewable genetic repository which will provide resources to all WGET investigators and to explore the relationship between the WG diathesis and genetic polymorphisms in candidate molecules, selected for their role in pathophysiology. We also propose to discover new polymorphisms in such molecules and apply these to this cohort. Accordingly, our specific aims are: 1) To establish a renewable biological resource of all WG patients screened and enrolled in the WGET clinical trial, including two ethnically and geographically matched controls for each patient; 2) To determine if known variations in genes involved in the innate inflammatory response, in lymphocyte activation and in target antigen biology influence the susceptibility to or severity of WG; 3) Recognizing that the knowledge base about biologically significant genetic variants will increase, we will determine, through direct discovery and through continual evaluation of SNP databases, if newly identified variation in gene categories outline in Specific Aim 2 influence the susceptibility to or severity of WG.